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Developing glutathione-activated catechol-type diphenylpolyenes as small molecule-based and mitochondria-targeted prooxidative anticancer theranostic prodrugs.
- Source :
-
Free radical biology & medicine [Free Radic Biol Med] 2019 Apr; Vol. 134, pp. 406-418. Date of Electronic Publication: 2019 Jan 29. - Publication Year :
- 2019
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Abstract
- Developing concise theranostic prodrugs is highly desirable for personalized and precision cancer therapy. Herein we used the glutathione (GSH)-mediated conversion of 2,4-dinitrobenzenesulfonates to phenols to protect a catechol moiety and developed stable pro-catechol-type diphenylpolyenes as small molecule-based prooxidative anticancer theranostic prodrugs. These molecules were synthesized via a modular route allowing creation of various pro-catechol-type diphenylpolyenes. As a typical representative, PDHH demonstrated three unique advantages: (1) capable of exploiting increased levels of GSH in cancer cells to in situ release a catechol moiety followed by its in situ oxidation to o-quinone, leading to preferential redox imbalance (including generation of H <subscript>2</subscript> O <subscript>2</subscript> and depletion of GSH) and final selective killing of cancer cells over normal cells, and is also superior to 5-fluorouracil and doxorubicin, the widely used chemotherapy drugs, in terms of its ability to kill preferentially human colon cancer SW620 cells (IC <subscript>50</subscript> = 4.3 μM) over human normal liver L02 cells (IC <subscript>50</subscript> = 42.3 μM) with a favourable in vitro selectivity index of 9.8; (2) permitting a turn-on fluorescent monitoring for its release, targeting mitochondria and therapeutic efficacy without the need of introducing additional fluorophores after its activation by GSH in cancer cells; (3) efficiently targeting mitochondria without the need of introducing additional mitochondria-directed groups.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- Antineoplastic Agents chemistry
Colonic Neoplasms metabolism
Colonic Neoplasms pathology
Humans
Mitochondria pathology
Oxidants chemistry
Oxidation-Reduction
Polyenes chemistry
Prodrugs chemistry
Small Molecule Libraries pharmacology
Theranostic Nanomedicine
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
Catechols chemistry
Colonic Neoplasms drug therapy
Glutathione pharmacology
Mitochondria drug effects
Oxidants pharmacology
Polyenes pharmacology
Prodrugs pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4596
- Volume :
- 134
- Database :
- MEDLINE
- Journal :
- Free radical biology & medicine
- Publication Type :
- Academic Journal
- Accession number :
- 30707929
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2019.01.033